PLGA Nanoplatform for the Hypoxic Tumor Delivery: Folate Targeting, Therapy, and Ultrasound/Photoacoustic Imaging.

Effective targeting of breast tumors is critical for improving therapeutic outcomes in breast cancer treatment. Additionally, hypoxic breast cancers are difficult to treat due to resistance toward chemotherapeutics, poor vascularity, and enhanced angiogenesis, which complicate effective drug delivery and therapeutic response. Addressing this formidable challenge requires designing a drug delivery system capable of targeted delivery of the anticancer agent, inhibition of efflux pump, and suppression of the tumor angiogenesis. Here, we have introduced Palbociclib (PCB)-loaded PLGA nanoparticles (NPs) consisting of chitosan-folate (CS-FOL) for folate receptor-targeted breast cancer therapy. The developed NPs were below 219 nm with a smooth, spherical surface shape. The entrapment efficiencies of NPs were achieved up to 85.78 ± 1.8%. Targeted NPs demonstrated faster drug release at pH 5.5, which potentiated the therapeutic efficacy of NPs due to the acidic microenvironment of breast cancer. In vitro cellular uptake study in MCF-7 cells confirmed the receptor-mediated endocytosis of targeted NPs. In vivo ultrasound and photoacoustic imaging studies on rats with hypoxic breast cancer showed that targeted NPs significantly reduced tumor growth and hypoxic tumor volume, and suppressed angiogenesis.

Redox-Sensitive Poly(lactic-co-glycolic acid) Nanoparticles of Palbociclib: Development, Ultrasound/Photoacoustic Imaging, and Smart Breast Cancer Therapy.

Breast cancer is one of the leading causes of mortality in women globally. The efficacy of breast cancer treatments, notably chemotherapy, is hampered by inadequate localized delivery of anticancer agents to the tumor site, resulting in compromised efficacy and increased systemic toxicity. In this study, we have developed redox-sensitive poly(lactic-co-glycolic acid) (PLGA) nanoparticles for the smart delivery of palbociclib (PLB) to breast cancer. The particle size of formulated PLB@PLGA-NPs (nonredox-sensitive) and RS-PLB@PLGA-NPs (redox-sensitive) NPs were 187.1 ± 1.8 nm and 193.7 ± 1.5 nm, respectively. The zeta potentials of nonredox-sensitive and redox-sensitive NPs were +24.99 ± 2.67 mV and +9.095 ± 1.87 mV, respectively. The developed NPs were characterized for morphological and various physicochemical parameters such as SEM, TEM, XRD, DSC, TGA, XPS, etc. The % entrapment efficiency of PLB@PLGA-NPs and RS-PLB@PLGA-NPs was found to be 85.48 ± 1.29% and 87.72 ± 1.55%, respectively. RS-PLB@PLGA-NPs displayed a rapid drug release at acidic pH and a higher GSH concentration compared to PLB@PLGA-NPs. The cytotoxicity assay in MCF-7 cells suggested that PLB@PLGA-NPs and RS-PLB@PLGA-NPs were 5.24-fold and 14.53-fold higher cytotoxic compared to the free PLB, respectively. Further, the cellular uptake study demonstrated that redox-sensitive NPs had significantly higher cellular uptake compared to nonredox-sensitive NPs and free Coumarin 6 dye. Additionally, AO/EtBr assay and reactive oxygen species analysis confirmed the superior activity of RS-PLB@PLGA-NPs over PLB@PLGA-NPs and free PLB. In vivo anticancer activity in dimethyl-benz(a)anthracene-induced breast cancer rats depicted that RS-PLB@PLGA-NPs was highly effective in reducing the tumor size, hypoxic tumor, and tumor vascularity compared to PLB@PLGA-NPs and free PLB. Further, hemocompatibility study reveals that the developed NPs were nonhemolytic to human blood. Moreover, an in vivo histopathology study confirmed that both nanoparticles were safe and nontoxic to the vital organs.

PTSA-induced synthesis, in silico and nano study of novel ethylquinolin-thiazolo-triazole in cervical cancer.

Aim: p-Toluenesulfonic acid-(PTSA) and grinding-induced novel synthesis of ethylquinolin-thiazolo-triazole derivatives was performed using green chemistry. Materials & methods: Development of a nanoconjugate drug-delivery system of ethylquinolin-thiazolo-triazole was carried out with D-α-tocopheryl polyethylene glycol succinate (TPGS) and the formulation was further characterized by transmission electron microscopy, atomic force microscopy, dynamic light scattering and in vitro drug release assay. The effect of 3a nanoparticles was assessed against a cervical cancer cell line (HeLa) through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the effect on apoptosis was determined. Results & discussion: The 3a nanoparticles triggered the apoptotic mode of cell death after increasing the intracellular reactive oxygen level by enhancing cellular uptake of micelles. Furthermore, in silico studies revealed higher absorption, distribution, metabolism, elimination and toxicity properties and bioavailability of the enzyme tyrosine protein kinase. Conclusion: The 3a nanoparticles enhanced the therapeutic potential and have higher potential for targeted drug delivery against cervical cancer.

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Epidemiology of Paediatric Trauma During National Lockdown: A Retrospective Study With 12 Months of Follow-Up.

Introduction The COVID-19 pandemic and its associated preventative measures such as national lockdown dramatically changed the daily activities of children. This paper aims to compare the epidemiology of paediatric orthopaedic trauma presentation, management and outcomes during the school closure period with the matched pre-pandemic period in 2019. Methods This was a retrospective cohort study of data collected from the West Yorkshire Trauma Network, comprising a major trauma centre, Leeds General Infirmary, and five peripheral trauma units. All patients aged 0-18 years who required trauma unit management during the school closure period (18 March 2020-25 May 2020) were included. Cases for the matched period in 2019 were analysed for baseline comparison. Patient demographics, mechanism and anatomical location of injury, management and follow-up were assessed. Results In the 2020 and 2019 cohorts, 286 and 575 injuries were observed, respectively. In the 2020 cohort, we observed a 50.3% (n=289) fall in paediatric trauma presentation and a significant proportional reduction in referrals from the emergency department (22% (n=63) versus 53% (n=305); p<0.001). There was also a significant reduction in the average age at presentation by more than one year (p<0.001). Sports-related injuries decreased significantly (n=16 (5.6%) versus n=127 (22.1%); p<0.001). While the proportion of ride-on injuries increased significantly, overall numbers remained similar (n=63 (22%) versus n=61 (10.6%); p<0.0001). Non-accidental injury (NAI) concerns rose significantly (n=9 (3.1%) versus n=4 (0.7%); p=0.01), but the absolute number of confirmed NAI cases stayed the same (n=2). There was a proportional increase in upper limb injuries (64.3% (n=184) versus 58.4% (n=336); p>0.05) and a proportional reduction in lower limb injuries (32.1% (n=92) versus 35.5% (n=204); p>0.05). However, the rate of tibial shaft injuries rose significantly (10.1% (n=29) versus 5.2% (n=30); p=0.02). The use of conservative management increased with a significant delay in average time to surgery from the date of injury (8.5 days versus 3.1 days; p=0.01). Patients who were only followed up with a telephone consultation rose significantly (23% (n= 66) versus 6% (n=35); p<0.001). Re-presentation rate increased significantly (1.4% (n=4) versus 0.2% (n=12); p=0.04). Conclusion Our study showed a reduction in paediatric trauma presentations during the pandemic and a significant reduction in the average age at presentation. This change has been accompanied by a shift in the mechanism and anatomical location of injury, management and subsequent follow-up.